The Sculpting of theMycobacterium tuberculosisGenome by Host Cell–Derived Pressures

Abstract

Mycobacterium tuberculosis is an incredibly successful pathogen with an extraordinary penetrance of its target host population. The ability to infect many yet cause disease in few is undoubtedly central to this success. This ability relies on sensing and responding to the changing environments encountered during the course of disease in the human host. This chapter discusses these environmental cues and stresses, and explores how the genome of Mtb has evolved under the purifying selections that they exert. In analyzing the response of Mtb to a broad range of intracellular pressures it is clear that, despite genome down-sizing, Mtb has retained an extraordinary flexibility in central carbon metabolism. We believe that it is this metabolic plasticity, more than any of the virulence factors, that is the foundation for Mtb’s qualities of endurance.

Multi-Omics Technologies Applied to Tuberculosis Drug Discovery

“…This is likely due to functional redundancy; for example, purT and purN both offer alternative pathways for purine de novo biosynthesis and so neither gene was essential [15], providing valuable information that allows non-essential targets to be dropped from drug discovery portfolios. A fundamental pathogenic trait of M.tb is the ability to survive and replicate in phagocytes, avoiding phagosome-lysosome fusion and adapting to an intracellular lifestyle [16]. Therefore, to define pathways that are essential for intra-macrophage survival, Barczak et al mapped genes required for intracellular growth using high content imaging alongside multiplexed cytokine analysis of macrophages infected with M.tb Tn mutant libraries [17].…”

Structure of the Essential Mtb FadD32 Enzyme: A Promising Drug Target for Treating Tuberculosis

“…Most TB infections originate in the lungs via inhalation of Mtb -containing aerosolized droplets from an actively infected individual, but extrapulmonary involvement is also common. Mtb has extraordinary metabolic plasticity that allows it to endure under a wide variety of conditions and external stresses, it can evade immune surveillance, and it exists largely in granulomatous lesions, whose heterogeneous nature is believed to contribute to differential drug susceptibility. − Consequently, TB is extremely difficult to treat relative to other bacterial infections, and chemotherapy for the simplest drug-sensitive TB requires a four-drug regimen composed of isoniazid, rifampicin, ethambutol, and pyrazinamide for 2 months, followed by a continuation phase of isoniazid and rifampicin for another 4 months. Multi-drug-resistant TB (MDR-TB) is defined as being resistant to both isoniazid and rifampin and requires the use of second-line TB drugs, which are generally less efficacious and have greater adverse effects.…”